Antacid material based on magnesium aluminium hydroxide and the preparation thereof

ABSTRACT

The present invention provides a process for the preparation of an antacid material based upon magnesium aluminium hydroxide, wherein magnesium hydroxide and/or magnesium oxide is reacted in an atomic ratio of magnesium to aluminium of 1:1 to 3:1 with an aqueous solution of aluminium sulphate until the pH of the reaction mixture is from 4.0 to 8.0, whereafter water-soluble components are removed from the mixture in known manner and this is isolated and, if desired, dried. 
     The present invention also provides pharmaceutical compositions containing an antacid material prepared by this process, in admixture with a conventional pharmaceutical adjuvant. 
     Furthermore, the present invention provides a method of combating hyperacidity and gastrointestinal diseases, which comprises administering an antacid material prepared by the above process.

This is a continuation of Application Ser. No. 260,859, filed May 6,1981 which is abandoned.

The present invention is concerned with an antacid material based onmagnesium aluminium hydroxide and with the preparation thereof.

Aluminum and magnesium hydroxides, especially in gel form, have provedto be effective antacids in the treatment of gastric hyperacidity and ofulcers.

However, the preparation of a practically useful antacid based uponaluminum magnesium hydroxide comes up against considerable difficultiessince a large variety of influences have a negative effect upon theeffectiveness or compatibility. An excess, in the physiological sense,of magnesium hydroxide, for example, gives rise not only to a rapidincrease of the pH value of the gastric juice above the neutral pointand thus induces a rebound effect, i.e. a really excessive production ofacid, but also exerts a strongly laxative action. An excess of aluminiumhydroxide, on the other hand, usually gives rise to undesirableconstipation.

In the case of conventional precipitation methods, bases, for examplesodium hydroxide, are also employed, the cations of which cannot becompletely removed from the voluminous gels by washing out and,consequently, these cations manifest their own undesired actions.However, sodium ions in particular must not be present in cases of highblood pressure and of diseases of the kidney and heart.

Because of the harmful effects of sodium ions, an attempt has been made,according to U.S. Pat. No. 4,105,579, to obtain aluminium hydroxide gelin pure form by precipitation from aluminium salts with an aqueoussolution of magnesium carbonate and subsequent filtration. In thismanner, it is admittedly possible to obtain a sodium-free aluminiumhydroxide gel but, for the above-mentioned reasons, it cannot be useddirectly as an antacid but must be admixed with a proportion ofmagnesium hydroxide.

According to Federal Republic of Germany Patent Specification No.2,327,768, aqueous ammonia is used as a precipitation agent for thepreparation of aluminium hydroxide. However, this process onlyapparently solves the problem since ammonium ions are alsophysiologically undesirable and, in the same way as alkali metal ions,are stubbornly held by the gel.

As is also known from Federal Republic of Germany Patent SpecificationNo. 1,617,277 (column 2, lines 55-63), it is extremely difficult to dryaluminium and magnesium hydroxide gels without their losing aconsiderable part of their acid-binding activity. In the case ofaluminium hydroxide gels, this disadvantage is even regarded as being acharacteristic.

It is an object of the present invention to provide an antacid materialwhich, apart from aluminium and magnesium, contains no other cationsand, in a dry state, even after comparatively prolonged storage, doesnot lose its acid-binding buffering capacity and which has an unusuallylong period of action, without deviating from the ideal buffer zone offrom about pH 3 to pH 5 at any time during the treatment therewith.

This object is, surprisingly, achieved by using solid magnesiumhydroxide and/or magnesium oxide for precipitating aluminium hydroxidefrom an aqueous solution of aluminium sulphate [Al₂ (SO₄)₃ ], theproduct obtained, after the removal of water-soluble components, beingisolated in known manner and, if desired, dried.

The starting materials are used in an atomic ratio of magnesium toaluminium of 1:1 to 3:1 and preferably of 1.3:1 to 2:1.

The precipitation reaction is finished when the reaction mixture hasreached a pH value of from 4.0 to 8.0 and preferably of from pH 5.0 topH 7.0.

According to U.S. Pat. No. 3,239,416, an attempt has already been madeto react a basic aluminium chloride [Al₂ (OH)₂ Cl₄ or Al₂ (OH)₅ Cl] withappropriate non-toxic alkaline earth metal compounds. However, due tothe presence of hydroxyl groups in the aluminium complex, across-linking in the end product is only partly possible. Consequently,a gel-like precipitate, a so-called co-gel, is obtained, the propertiesof which differ considerably from those of the end product obtainedaccording to the present invention and which, in addition, must be freedfrom undesired chloride ions by repeated and laborious washing.Furthermore, in order to achieve a suitable pH value for the reaction,the addition of sodium carbonate or sodium bicarbonate is usuallynecessary when carrying out this known process.

A similar proposal, which by-passes the object of the present invention,has also been disclosed in Chemical Abstracts, 83, 8485e/1975. In thiscase, too, a pre-hydrolysed polybasic aluminium sulphate of limitedreactivity is reacted with magnesium hydroxide. Due to the hydrolysiswith sodium bicarbonate, undesired sodium ions are entrained which canscarcely be removed from the resultant gel.

In U.S. Pat. No. 4,105,579, a process is described for the preparationof a more or less pure aluminium hydroxide by precipitation fromaluminium chloride solutions (or, alternatively, also nitrate andsulphate) by means of an alkaline earth metal carbonate, undesiredamounts of carbonate thereby getting into the end product.

Therefore, according to the present invention, there is provided aprocess for the preparation of an antacid material based upon magnesiumaluminium hydroxide, wherein magnesium hydroxide and/or magnesium oxideis reacted in an atomic ratio of magnesium to aluminium of 1:1 to 3:1with an aqueous solution of aluminium sulphate until the pH of thereaction mixture is from 4.0 to 8.0, whereafter water-soluble componentsare removed from the mixture in known manner and this is isolated and,if desired, dried.

After complete removal of the readily watersoluble components, a productis obtained with the following properties:

1. the atomic ratio of aluminium to magnesium is from 0.5:1 to 7:1 andpreferably from 1:1 to 6:1;

2. the pH value of an aqueous suspension thereof is from 5.5 to 9.0 andpreferably from 6.0 to 8.5;

3. a dose of the product prepared according to the present inventionwith 20 mMol aluminium reaches, in the case of the determination of theacid-binding capacity by Schaub's method (see Pharm. Acta Hlev., 38,16/1963), a pH value of 3.5 after only 1 minute; in most cases, the pHvalue does not exceed 4.5 and in all cases it is below 5.0 and, in spiteof the addition of Schaub's simulated gastric juice, it remains above pH3.0 for at least 120 minutes and, in many cases, for up to 160 minutes;

4. the active material obtained only contains the physiologicallycompatible cations present in the starting materials and, as anions,only contains sulphate and hydroxyl ions and is, therefore, alsosuitable for high-dosage antacid therapy.

Thus, according to the present invention, it is possible, with verysimple means and without the use of foreign additives, to prepare ahighly effective antacid material which, according to present dayknowledge, displays an ideal activity profile. In particular, itpossesses the following properties which are demanded of an idealantacid and is, therefore, superior to the known antacids:

1. the action commences immediately without an increased gastric acidsecretion and a rebound effect resulting due to exceeding the admissiblelimit of pH 5;

2. the buffering of the gastric juice within the narrow ideal range offrom pH 3 to pH 5 is maintained for at least 2 hours:

3. the antacid reduces the pepsin activity without, however, completelyinhibiting it;

4. the antacid does not have any harmful side effects since themagnesium and aluminium ions are in a balanced ratio to one another andno undesired foreign cations, such as sodium, calcium, ammonium bismuthand the like, and no undesired anions, such as chloride, carbonate andthe like, are present;

5. the antacid also binds bile acids which play a part in the genesis ofhaemorrhagic gastritis and of ulcers;

6. the active material is stable, also retains its buffer capacity indry form for a long time and has a completely neutral taste;

7. a safe preservation for the avoidance of microbial growth is possiblein suspensions of this antacid material because of its optimum pH range;

8. in contradistinction to known gels, the antacid is obtained in theform of a powder which can be easily filtered or centrifuged and canalso be very readily further worked up.

The process of preparation according to the present invention gives ahydroxide mixture or a hydroxide/oxide mixture in which the strongbasicity of the magnesium hydroxide or oxide component is initiallyfully masked by the aluminium hydroxide gel precipitated from thesolution so that this only acts slowly.

This leads to a previously unachieved flattening of the pH curve of thegastric juice which, in the case of the known hydroxide mixtures, alwaysdisplays, shortly after administration, a distinct maximum above pH 5but, in the present case, proceeds very flatly and always below pH 5.

A precise chemical analysis of the structure of the antacid materialaccording to the present invention has hitherto not been carried out.However, it is assumed that the sulphate ion, due to its divalency,forms bridges and thus possibly sparingly soluble basic mixed salts,which hold firmly bound a more or less large proportion of the sulphateanions but which are physiologically completely compatible. Whether thisproportion of anions is partly responsible for the outstandingphysiological properties of the antacid prepared according to thepresent invention or whether this depends preponderantly upon theheterogenous precipitation method used and a covering of the basicmagnesium hydroxide by aluminium hydroxide or by its mixed saltspossibly resulting thereby, has not yet been elucidated. However, it hasbeen shown that the sulphate content also positively influences thephysical properties, for example to good filterability.

It must be observed that the ideal atomic ratio of aluminium tomagnesium depends upon the starting materials. In the case of too greatan excess of aluminium salt, the magnesium hydroxide can be completelydissolved; the yield of antacid material is then at least small and sucha fine precipitate is formed that separation thereof becomes difficult.In the case of too great an excess of magnesium hydroxide or oxide, aprecipitate is admittedly obtained which can be easily separated but theproduct then assumes more and more the undesired properties of puremagnesium hydroxide and the kinetics of the acid-binding capacity(according to Schaub) deteriorate. At the commencement of treatment withsuch an antacid, a pH maximum above pH 5 then distinctly occurs, whichis typical for magnesium hydroxide or oxide.

The atomic ratio in the antacid end product is determined by thequantitative atomic ratio of aluminium to magnesium in the startingmaterials. By the choice of a particular atomic ratio, it is very easyto adjust an atomic ratio of aluminium to magnesium in the antacid endproduct within the preferred range of from 0.5:1 to 7:1. The particlesize of the magnesium hydroxide or magnesium oxide used as startingmaterial is preferably from 10 to 50 μm.

The amounts of water used also have an influence upon the physicalproperties of the antacid product. In this regard, care should be takenthat the concentration of the aluminium sulphate solution and of themagnesium hydroxide or oxide suspension is not too high since theproduct can otherwise only be filtered off with difficulty. It ispreferred to use a 0.2 to 0.3 molar aqueous aluminium sulphate solutionand an approximately 1 molar magnesium hydroxide suspension as startingmaterials.

For the process of preparation, it is immaterial whether the aluminiumsulphate in solution is added to a slurry of the magnesium hydroxide ormagnesium oxide or whether the reverse procedure is used and themagnesium hydroxide or oxide slurry is introduced into the solution ofthe aluminium sulphate. However, it is important continuously to monitorthe pH value of the reaction mixture after mixing the reactioncomponents together and to stir the mixture until the desired pH valuehas been obtained.

Since the aluminium content in the end product increases with anincreasing period of stirring at the expense of the magnesium content,it is also possible to control the mole ratio to a certain extent by theperiod of reaction. The acidic pH value in the reaction mixtureinitially increases very quickly and then asymptotically approaches theend value. For an appropriate quality of the antacid material, thecomponents should be reacted together at least until a pH of from 4 to 8is reached. The reaction can be accelerated by increasing thetemperature, without changing the end product. However, the temperatureshould not exceed 60° C.

At the end of the reaction, water-soluble magnesium salts can be veryeasily removed by washing out. Even after a single washing of thefiltered off antacid material, less than 2% of the dissolved materials(referred to the dried product) are present in the first wash water. Thesoluble and non-toxic salts are thus removed from the antacid materialto such an extent that this can be used directly.

In practice, the product is washed twice at most. The sulphate contentof the antacid product, dried for 4 hours at 110° C. is in the range offrom 5 to 25% and preferably of from 10% to 20%.

For the determination of the optimum molar atomic ratio (i.e. in the endproduct, the longest possible buffering time above pH 3.0 and noincrease of the pH value above 5.0 in the case of determining theacid-binding capacity by Schaub's method) of magnesium to aluminium inthe starting materials, a series of experiments is carried out. The sameamounts of magnesium hydroxide are thereby reacted with increasingamounts of aluminium sulphate under otherwise the same reactionconditions.

The following Table summarises the results of this series ofexperiments. The experiments were carried out as follows:

2 g. Magnesium hydroxide were suspended in 18 g. of water. Aluminiumsulphate octadecahydrate was weighed out in a molar ratio and dissolvedin sufficient water to give 80 g. of solution. The solution was thenadded, with stirring, to the magnesium hydroxide suspension. Thereaction mixture was stirred for 3 hours, during which time the pH valueof the reaction mixture was continuously measured. The precipitateobtained was filtered off through a G3 frit under reduced pressure andwell washed twice with 50 ml. amounts of water. Subsequently, theproduct was well dried by passing air therethrough. Finally, the antacidproduct obtained in this manner was examined for its acidbindingcapacity by Schaub's method (Pharm. Acta Helvetica, 38, 16/1963). Theresults of the experiments are given in the following Table:

                                      TABLE                                       __________________________________________________________________________    Experimental series of Mg(OH).sub.2 with Al.sub.2 (SO.sub.4).sub.3.18H.sub    .2 O                                                                                    pH value of                                                                   the reaction                                                        atomic ratio Mg:Al                                                                      mixture at                                                                           yield after                                                                          acid-binding capacity                                 in the starting                                                                         the end of                                                                           drying buffering time                                                                       pH value peak                                  materials the reaction                                                                         110° C./4 hrs.                                                                above pH 3.0                                                                         after 20 minutes                               __________________________________________________________________________    1 Mg:0.60 Al                                                                            6.0    2.18 g.                                                                              140 min.                                                                             5.1                                            1 Mg:0.65 Al                                                                            6.0    2.59 g.                                                                              150 min.                                                                             5.0                                            1 Mg:0.70 Al                                                                            5.7    2.67 g.                                                                              150 min.                                                                             4.1                                            1 Mg:0.75 Al                                                                            5.4    2.79 g.                                                                              150 min.                                                                             3.9                                            1 Mg:0.80 Al                                                                            4.2    3.05 g.                                                                              160 min.                                                                             3.6                                            1 Mg:0.85 Al                                                                            4.0    2.50 g.                                                                              120 min.                                                                             3.8                                            __________________________________________________________________________

The atomic ratio was calculated as follows:

    ______________________________________                                        2 g. Mg(OH).sub.2 =                                                                          0.03429 mol Mg                                                 8 g. Al.sub.2 (SO.sub.4).sub.3.18H.sub.2 O =                                                 0.01200 mol Al.sub.2 (SO.sub.4).sub.3.18H.sub.2 O              =              0.02400 mol Al                                                                which corresponds to an atomic                                                ratio in the starting materials                                               of magnesium to aluminium of 1:0.7.                            ______________________________________                                    

If the amounts of aluminium sulphate are too low, the disadvantageousproperties of magnesium hydroxide with regard to acid-binding capacityoccur, i.e. the pH value peak is above 5.0.

If the amount of aluminium sulphate is too great, the magnesiumhydroxide can be completely dissolved and only aluminium hydroxide ispresent as a gel, which is difficult to filter, or, in extreme cases,only a clear solution is obtained.

The most favourable atomic ratio can be easily determined by evaluationof the values for yield, buffering time and pH value peak. Those atomicratios are selected within the preferred pH range (pH value peak) withwhich, in the case of the most favourable yields, there is associatedthe longest buffering time.

Gel-like aluminium or magnesium hydroxides prepared by precipitationare, because of their structure, extremely difficult to filter.Surprisingly, we have found that the process according to the presentinvention does not suffer from this disadvantage and, especially in thepreferred process ranges, gives a product which is excellent to filterand is capable of elution. This is a further considerable technicaladvantage over the prior art.

The antacid product according to the present invention can, after gentledrying, be worked up directly in known manner to give solid compositionsfor oral administration, for example capsules, dragees, granulates or,preferably, tablets. For the production of solid compositions for oraladministration, use is made, in the conventional manner, of adjuvant andcarrier materials, for example starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weightfatty acids (for example stearic acid) and the salts or esters thereof,gelatine, agar-agar, animal and vegetable fats and solid high molecularweight polymers (for example polyethylene glycol). If desired, thecompositions can also additionally contain flavouring and/or sweeteningagents. The composition is preferably so dosed that one dosage unitcontains 0.3 to 1.0 g. of antacid product. 1 to 2 Units of thiscomposition can be administered several times a day at intervals of 1 to2 hours since it is completely non-toxic.

The antacid product according to the present invention is, in a moist ordry state, also outstandingly useful for the production of suspensions,in which case, in addition to the above-mentioned adjuvants, thickeningagents and conventional suspension stabilisers are also added.Suspensions are generally the preferred form of administration forantacids, for which reason they are also especially preferred accordingto the present invention.

The liquid forms of administration can contain, per milliliter, about0.1 to 0.2 g. of antacid product. There are thus obtained dosage unitsof about 6 ml., which correspond to one teaspoonful. Here, too,depending upon the severity of the disease picture, 1 to 2 dosage unitscan be administered at intervals of 1 to 2 hours during the course ofthe day.

The antacid product according to the present invention can also beworked up in a moist state as a liquid pharmaceutical form so thatdrying measures can be omitted.

The active material according to the present invention also possessesthe great advantage that it can be preserved with conventionalpreservation agents which are practically only effective in a weaklyacidic to neutral pH range. As described above, aqueous suspensions ofthe active material are characterised by a weakly acidic to weakly basicpH range, whereas all previously known compositions have, as far as isknown, a distinctly basic pH value. Thus, for example, the activematerial according to the present invention can be preserved in aqueoussuspension by, for example, sorbic acid, benzoic acid or PHB ester,which lose their effectiveness in the basic region.

For the production of solid pharmaceutical forms, a gentle dryingprocess should be used, i.e. the thermal stressing should be as small aspossible.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1

0.012 mol aluminium sulphate with variable amounts of water ofcrystallisation are dissolved, while stirring, in 42 ml. of water, withgentle heating up to about 50° C. 0.034 mol magnesium hydroxide,suspended in 30 ml. of water, are slowly added, with vigorous stirring,to the aluminium sulphate solution. After complete addition of thesuspension, the reaction mixture is stirred (about 1 hour) until theaqueous suspension has reached a pH value of 5.5. The mixture is thenfiltered under reduced pressure through a G3 frit and, withresuspension, washed twice with 50 ml. amounts of water. After filteringoff, the precipitate is dried, first at ambient temperature and then for4 hours at 60° C. The yield is 3.0 g. The pH value of an aqueoussuspension of the product is 6.0.

    ______________________________________                                        Composition:                                                                            0.02 mol aluminium                                                            0.005 mol magnesium                                                           Acid-binding capacity by Schaub's method:                                     buffering time (above pH 3.0) = 150 minutes                                   pH value after 20 minutes = 4.1                                     ______________________________________                                    

The course of the acid-binding capacity under different conditions isgiven in FIGS. 1 and 2 of the accompanying drawings.

EXAMPLE 2

1 kg. Magnesium hydroxide is suspended in 14 kg. of water. To thissuspension is added a solution, prepared at 60° C., of 4 kg. aluminiumsulphate octadecahydrate in 21 liters of water, while stirring. Afterstirring for 3 hours, the reaction mixture has a pH of 5.8. The reactionmixture is then filtered off under reduced pressure and washed twice,with resuspension, with 15 liter amounts of water and dried in the air.Yield 3.5 kg.

EXAMPLE 3

22.3 g. Aluminium sulphate octadecahydrate are dissolved in 750 g. ofwater. Subsequently, 60 g. magnesium hydroxide in pulverised form aresprinkled in, while stirring. Stirring is continued until the reactionmixture has a pH value of 4.7. The precipitate is filtered off underreduced pressure through a G3 glass frit, then well washed twice withabout 200 ml. amounts of water and subsequently dried by passing throughair. The yield is about 480 g.

EXAMPLE 4

39 g. Magnesium oxide are suspended in 0.5 liters of water. At the sametime, 240 g. aluminium sulphate octadecahydrate are dissolved in 0.7liters of water and subsequently added, while stirring, to the magnesiumoxide suspension. The mixture is stirred until a pH value of 4.3 isreached. After washing twice with 200 ml. amounts of water, the productis filtered off and dried at 30° C. The yield is 300 g.

FIGS. 1 to 3 of the accompanying drawings illustrate the acid-bindingcapacities (by Schaub's method) of the product of Example 1 and of acomparison mixture.

FIG. 1 shows the acid-binding capacity of the product of Example 1 at adosage of 3 g. and 4.5 g. of dry substance. It can be seen that, afterabout 15 minutes, a very flat pH maximum of about pH 4.4 is reachedwith, after a further 15 minutes, runs practically in a straight line. Adistinct pH drop can only be seen after about 130 or 180 minutes(Table).

FIG. 2 shows a comparative curve of the product according to Example 1from which it can be seen that a product stored for 3 months shows onlya slight loss of activity.

FIG. 3 shows the course of the curve of the acid-binding capacity of aconventional mixture consisting of 5 mMol magnesium hydroxide and 20mMol aluminium hydroxide gel. The undesired pH maximum can be clearlyseen and, in the case of the preparation which is 24 hours old, the pHof 5 is exceeded after only 5 minutes. It can also be seen that the pHvalue drops again to below 3 in less than an hour.

We claim:
 1. A process for the preparation of an antacid material basedupon magnesium aluminum hydroxide, substantially free of sodium andcarbonate ions, which comprises reacting a magnesium compound selectedfrom the group of magnesium hydroxide, magnesium oxide, or mixturesthereof in an atomic ratio of magnesium to aluminum of 1:1 to 3:1 withan aqueous solution of aluminum sulphate until the pH of the reactionmixtures is from 4.0 to 8.01, then removing water-soluble componentsfrom the mixture and, isolating said antacid material.
 2. A processaccording to claim 1, wherein the starting materials are used in anatomic ratio of magnesium to aluminium of 1.3:1 to 2:1.
 3. A processaccording to claim 1 wherein the reaction is terminated when the pH ofthe reaction mixture is from 5.0 to 7.0.
 4. A process according to claim1 wherein the reaction is carried out at a temperature which does notexceed 60° C.
 5. A process according to claim 2 wherein the reaction isterminated when the pH of the reaction mixture is from 5.0 to 7.0.
 6. Aprocess according to claim 5 wherein the reaction is carried out at atemperature which does not exceed 60° C.
 7. A process according to claim2 wherein the reaction is carried out at a temperature which does notexceed 60° C.
 8. A process according to claim 3 wherein the reaction iscarried out at a temperature which does not exceed 60° C.
 9. The processof claim 1 which further comprises drying said antacid material andwherein said antacid material is free of sodium and carbonate ions.